Stroke is a major health problem in the US with 800,000 people killed or debilitated each year. Currently, there is only one treatment, which needs to be administered within the first three hours of stroke onset. Our laboratory is examining treatments that would extend this therapeutic window. Our studies have shown that effective post-stroke treatment must possess both neuroprotective and anti-inflammatory properties. We have found that activation of sigma receptors decrease infarct area by over 80% when delivered 24 hours post- stroke in the rat. These receptors decrease neuronal death by depressing ischemia-induced intracellular calcium elevations, increased neuroexcitability and acid-sensing ion channel activation. Sigma receptors activation is also anti-inflammatory by blocking activation, migration and release of inflammatory cytotoxins from microglia. The goal of this proposal is to extend our initial findings that sigma receptor activation is a useful stroke treatment at timepoints beyond the current three hour window. The initial studies will determine the proper dose and therapeutic window for these compounds following an ischemic insult. The proposed study examines behavioral recovery promoted by sigma receptor activation at delayed time points following an ischemic insult. Moreover, we will test the sigma receptor ligand opipramol in our stroke model. Opipramol has been used clinically for over 40 years in Europe, which would accelerate its progression to clinical trials. Sigma receptor agonists are potential compounds to treat stroke many hours to days after onset to arrest the expansion of ischemic area through increasing neurosurvival and blocking the inflammatory response. Stroke is a major health problem in the USA with only one FDA-approved treatment, which has a limited therapeutic window. Since there have been no advances in stroke therapies, innovative approaches are needed to discover new agents to combat this pathologic condition. We have found that systemic administration of DTG, a sigma receptor agonist, has neuroprotective and anti-inflammatory properties that protects against stroke-induced brain injury at 24 hours post-stroke in rats. This proposal will further examine the therapeutic capability of DTG in stroked rats. Another sigma receptor agonist, opipramol, will also be examined for its therapeutic effectiveness in stroke. Opipramol has been used in humans for over 40 years as an anxiolytic agent.